Atypical hemolytic and uremic syndrome due to C3 mutation in pancreatic islet transplantation: a case report.

BACKGROUND: We here report on the first observation of a C3 mutation that is related to atypical hemolytic and uremic syndrome (aHUS), which occurred in a pancreatic islet transplant patient. Immunosuppressive treatments, such as calcineurin inhibitors, have been linked to undesirable effects like nephrotoxicity. CASE PRESENTATION: A 40-year-old man with brittle diabetes, who was included in the TRIMECO trial, became insulin-independent 2 months after pancreatic islet transplantation. About 15 months after islet transplantation, the patient exhibited acute kidney injury due to aHUS. Despite plasma exchange and eculizumab treatment, the patient developed end-stage renal disease. A genetic workup identified a missense variant (p.R592Q) in the C3 gene. In vitro, this C3 variant had defective Factor I proteolytic activity with membrane proteins as cofactor proteins, which was thus classified as pathogenic. About 1 year after the aHUS episode, kidney transplantation was carried out under the protection of the specific anti-C5 monoclonal antibody eculizumab. The patient had normal kidney function, with preserved pancreatic islet function 4 years later. CONCLUSIONS: Pancreatic islet transplantation could have triggered this aHUS episode, but this link needs to be clarified. Although prophylactic eculizumab maintains kidney allograft function, its efficacy still needs to be studied in larger populations.

Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review.

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.

[Clinical efficacy of eculizumab as treatment of gemcitabine-induced thrombotic microangiopathy: A case report]. / Efficacité de l'éculizumab comme traitement de la microangiopathie thrombotique induite par la gemcitabine : à propos d'un cas.

INTRODUCTION: Gemcitabine-induced thrombotic microangiopathy is a rare event whose management is not yet consensual. The use of eculizumab could be of interest. CASE REPORT: A 68-year-old woman was treated by gemcitabine as adjuvant chemotherapy of a pancreatic adenocarcinoma. Two months later, the patient presented with mechanical hemolytic anemia, thrombocytopenia and high blood pressure that led to the diagnosis of thrombotic microangiopathy. Gemcitabine was stopped. Plasma exchange therapy was introduced since hematological and renal parameters had worsened. As clinical efficacy was insufficient, eculizumab was introduced at a dose of 900 mg per week 4 times, then 1200 mg every 2 weeks. Symptoms along with hematological and nephrological analysis were back to physiological standards after 7 intravenous injections. CONCLUSION: Eculizumab seems to be an effective treatment against gemcitabine-induced thrombotic microangiopathy in case of severe hematological and renal injuries associated with a lack of response to plasma exchange therapy.